Autonomous growth of a human neuroblastoma cell line is mediated by insulin-like growth factor II.

El-Badry, Ossama M.; Romanus, Joyce A.; Helman, Lee J.; Cooper, Mark J.; Rechler, Matthew M.; Israel, Mark A.

doi:10.1172/jci114243

Cited by 169 publications

(91 citation statements)

References 60 publications

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“…As seen in many other cell lines with dysregulated IGF-I signaling, rhabdomyosarcoma cells are extremely susceptible to rapamycin in growth inhibition (IC 50 ¼ 1-3 nM) (Hosoi et al, 1998). Since IGFs (IGF-I and IGF-II) promote the motility of rhabdomyosarcoma cells (El-Badry et al, 1990;Minniti et al, 1992;Gallicchio et al, 2003), we determined whether rapamycin also inhibits motility of rhabdomyosarcoma cells. Using the wound-healing assay, we found that Rh1 and Rh30 (two rhabdomyo-sarcoma cell lines) migrated under autocrine (serum free) conditions as RD (another rhabdomyosarcoma cell line) cells did (El-Badry et al, 1990).…”

Section: Resultsmentioning

confidence: 91%

“…Rapamycin inhibits IGF-I or 10% fetal bovine serumstimulated cell motility Rhabdomyosarcoma cells were primarily chosen as models to study IGF-I-mediated cell motility, because dysregulation of IGF-I signaling has been well characterized in these childhood tumor cells (El-Badry et al, 1990;Minniti et al, 1992;Shapiro et al, 1994). There exist high levels of IGF-I receptor in RMS cells (Shapiro et al, 1994).…”

Section: Resultsmentioning

confidence: 99%

“…Since IGFs (IGF-I and IGF-II) promote the motility of rhabdomyosarcoma cells (El-Badry et al, 1990;Minniti et al, 1992;Gallicchio et al, 2003), we determined whether rapamycin also inhibits motility of rhabdomyosarcoma cells. Using the wound-healing assay, we found that Rh1 and Rh30 (two rhabdomyo-sarcoma cell lines) migrated under autocrine (serum free) conditions as RD (another rhabdomyosarcoma cell line) cells did (El-Badry et al, 1990). Rapamycin inhibited the basal or IGF-I-stimulated motility of Rh1 and Rh30 cells in a concentration-dependent manner (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…IGF-IR controls lung carcinoma cell motility and invasion by coordinately regulating expression and activation of matrix metalloproteinase-2 (Zhang and Brodt, 2002). IGFs are also potent stimulators of rhabdomyosarcoma cell motility (El-Badry et al, 1990;Minniti et al, 1992;Gallicchio et al, 2003). Therefore, IGF-I signaling contributes to metastatic phenotypes in various types of tumors.…”

Section: Introductionmentioning

confidence: 99%

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Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

et al. 2006

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Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), inhibits tumor cell motility. However, the underlying mechanism is poorly understood. Here, we show that rapamycin inhibited type I insulin-like growth factor (IGF-I)-stimulated motility of a panel of cell lines. Expression of a rapamycin-resistant mutant of mTOR (mTORrr) prevented rapamycin inhibition of cell motility. However, cells expressing a kinase-dead mTORrr remained sensitive to rapamycin. Downregulation of raptor or rictor by RNA interference (RNAi) decreased cell motility. However, only downregulation of raptor mimicked the effect of rapamycin, inhibiting phosphorylation of S6 kinase 1 (S6K1) and 4E-BP1. Cells infected with an adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6K1, but not with an adenovirus expressing wild-type S6K1, or a control virus, conferred to resistance to rapamycin. Further, IGF-I failed to stimulate motility of the cells, in which S6K1 was downregulated by RNAi. Moreover, downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) by RNAi-attenuated rapamycin inhibition of cell motility. In contrast, expression of constitutively active 4E-BP1 dramatically inhibited IGF-I-stimulated cell motility. The results indicate that both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell motility. Rapamycin inhibits IGF-I-stimulated cell motility, through suppression of both S6K1 and 4E-BP1/eIF4E-signaling pathways, as a consequence of inhibition of mTOR kinase activity.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

et al. 2006

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“…24 In some aggressive NB tumors as well as in many NB cell lines, autocrine production of IGF2 is detectable. 26 Recently, we demonstrated that IGFBP-5 transcription is stimulated by c-Myb and B-Myb oncoproteins in NB cells through direct and indirect mechanisms. 27 In the same cells, IGFBP-5 administration causes dose-dependent opposite effects: low amounts of recombinant protein added to the medium stimulated proliferation while a high concentration reduced cell growth.…”

Section: Introductionmentioning

confidence: 99%

Silencing of endogenous IGFBP-5 by micro RNA interference affects proliferation, apoptosis and differentiation of neuroblastoma cells

et al. 2004

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Signal transduction through the IGF axis is implicated in proliferation, differentiation and survival during development and adult life. The IGF axis includes the IGF binding proteins (IGFBPs) that bind IGFs with high affinity and modulate their activity. In neuroblastoma (NB), a malignant childhood tumor, we found that IGFBP-5 is frequently expressed. Since NB is an IGF2-sensitive tumor, we investigated the relevance and the function of endogenous IGFBP-5 in LAN-5 and in SY5Y(N) cell lines transfected with micro and small interfering RNAs directed to IGFBP-5 mRNA. Cells in which IGFBP-5 expression was suppressed were growth-inhibited and more prone to apoptosis than the parental cell line and controls. Apoptosis was further enhanced by X-ray irradiation. The ability of these cells to undergo neuronal differentiation was impaired after IGFBP-5 inhibition but the effect was reversed by exposure to recombinant IGFBP-5. Together, these data demonstrate the importance of IGFBP-5 for NB cell functions and suggest that IGFBP-5 might serve as a novel therapeutic target in NB.

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IGFBP-2 expression in a human cell line is associated with increased IGFBP-3 proteolysis, decreased IGFBP-1 expression and increased tumorigenicity

1998

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Insulin‐like growth factors (IGF‐I and ‐II) play an active role in cell proliferation. In biological fluids, they are non‐covalently bound to high‐affinity binding proteins (IGFBPs), at least 6 species of which have been identified to date, but with poorly defined functions. One of these IGFBPs, IGFBP‐2, is secreted by most cell lines and appears to be involved in cell proliferation. A human epidermoid carcinoma cell line, KB 3.1, which produces IGFBP‐1 and ‐3 and small amounts of IGFBP‐4, but no IGFBP‐2, was stably transfected with an expression vector comprising IGFBP‐2 complementary DNA (cDNA), whose expression was placed under the control of the constitutive and ubiquitous cytomegalovirus promoter. After an s.c. injection of these IGFBP‐2‐expressing KB 3.1 cells into nude mice, tumours developed more quickly than in controls, they were 3 to 4 times larger and grew about 3 times as fast. Concomitant with IGFBP‐2 expression in these tumours, were a decrease in IGFBP‐1 expression and an increase in IGFBP‐3 proteolysis, both of which increase the bioavailability of the IGF‐II produced by the cells. The increased IGFBP‐3 proteolysis most probably resulted from amplified expression of tissue‐type plasminogen activator (t‐PA) and depression of its inhibitor (PAI‐1) observed in IGFBP‐2‐expressing xenografts. Our findings suggest that IGFBP‐2 plays a role in this model of experimental tumorigenesis via a mechanism that remains unclear, but appears to involve increased protease activity and IGF‐II bioavailability. Int. J. Cancer 77:874‐879, 1998.© 1998 Wiley‐Liss, Inc.

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Autonomous growth of a human neuroblastoma cell line is mediated by insulin-like growth factor II.

Cited by 169 publications

References 60 publications

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

Silencing of endogenous IGFBP-5 by micro RNA interference affects proliferation, apoptosis and differentiation of neuroblastoma cells

IGFBP-2 expression in a human cell line is associated with increased IGFBP-3 proteolysis, decreased IGFBP-1 expression and increased tumorigenicity

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